22r - or 22s-epimer connection, the method of production thereof, pharmaceutical composition and method of treating allergic and inflammatory diseases

 

(57) Abstract:

The invention relates to compounds of General formula I in the form 22R and 22S-ephemerol, where X1and X2are the same or different and each represents a hydrogen atom or a fluorine atom, provided that X1and X2at the same time are not hydrogen atoms; methods for their preparation; pharmaceutical preparations containing them; and the use of these compounds in the treatment of inflammatory and allergic diseases. 3 S. and 6 C. p. F.-ly.

The invention relates to new anti-inflammatory and anti-allergic active compounds and to a process for their preparation. The invention also relates to pharmaceutical compositions containing these compounds, and pharmacological methods of using these compounds.

The purpose of the invention is the development of anti-inflammatory, immuno-suppressive and anti-allergic glucocorticosteroids or pharmaceutical compounds with high activity when applied topically, for example, in the respiratory tract, skin, gastrointestinal tract, joints or eyes: drug action aimed at unrestricted area targets, whereby induced weak glucocortico the local treatment of inflammatory, allergic or immunologic diseases in the respiratory tract (e.g. asthma, rhinitis), skin (eczema, psoriasis) or in the intestine (ulcerative colitis, diseases of Crohn). Local treatment with corticosteroids has clinical benefit to the General treatment (for example, using steroid tablets), especially in relation to reducing unwanted glucocorticosteroid effects outside the scope of the disease, by reducing the necessary dose. To achieve the same high clinical effect, for example, in the treatment of severe respiratory diseases, corticosteroids should possess suitable pharmacological profile. They should have high activity, characteristic of glucocorticosteroids, in the place of use, but also to quickly inaktivirovanie before or after absorption into the General circulation. Known derivatives pregnene-4, which has anti-inflammatory and antiallergic activity (EP 0054010 A1(Aktiebolaget Draco), 16.06.82, C 07 J 71/00).

One of the purposes of the invention is to provide new SCS connections. They are highly anti-inflammatory, immuno-suppressive and anti-anaphylactic efficiency at the application site; in private is e GKS outside the treated area.

Compounds of the invention are 22R - or 22S-epimerase compounds with the General formula:

< / BR>
where

X1and X2are the same or different, each is represented by hydrogen atom or halogen atom, provided that X1and X2at the same time are not hydrogen atoms.

Individuality 22R and 22S-epimeres by formula I can be set as follows - due to the chirality of the carbon atom in position 22:

< / BR>
< / BR>
where

X1and X2are the groups described above.

Epimere 22R and 22S, respectively, in formula I, above, are, by definition, compounds, the content of which does not exceed 2%, preferably not more than 1% by weight of another epimer.

Preferred compounds of the invention are 22R and 22S-epimer with structure:

< / BR>
Preferred steroid has the R-configuration at the 22nd carbon atom.

Preparation methods. 16,17-acetals of the formula I are obtained by reaction of the compound with the formula

< / BR>
where

X1and X2have this above definition, with the aldehyde in the formula

< / BR>
The reaction is performed by adding the steroid to a solution of aldehyde together with kislotno is, predpochtitelno, dioxane or acetonitrile.

Connection with formula I can also be obtained by transacetylase respective 16, 17-acetonide:

< / BR>
where

X1and X2have this above definition, with the aldehyde in the formula

< / BR>
The reaction is performed by adding the steroid to a solution of the aldehyde with an acid catalyst, for example, perchloric acid, p-toluene-acid, hydrochloric acid, dissolved in ether, preferably dioxane or acetonitrile.

The reaction can also be performed in the reaction medium, which is a hydrocarbon, preferably, isooctane, where the solubility pregnanolone derived (16,17-acetonide or 16,17-diol) is less than 1 mg/l, or a halogen-substituted hydrocarbon, preferably methylene chloride or chloroform.

The reaction is catalyzed halogenation acid or organic acid such as p-toluene-acid.

The reaction is performed in the presence of small grains of inert material, such as glass, ceramics, sifted silicon dioxide (sand) or particles of inert metal, such as powdered stainless steel and is the 22R-epimer formed almost exclusively, it is possible to obtain a sufficiently purified for use as a pharmaceutical substance by recrystallization instead of the more expensive chromatographic methods.

In the reaction in a hydrocarbon environment complex steroid-catalyst will form a large sticky clumps that make it impossible stirring and effective response.

To overcome this are little pellets of inert material and efficient mixing to prevent the formation of large lumps and, instead, divide the complex steroid-catalyst thin layers around the grains. Through this reactive surface will be much more, and reaction with the carbonyl compound will happen very quickly.

Grains of inert material used in this process, preferably, silicon dioxide (SiO2), should be a freely moving relative to each other tiny particles. The particle size is in the range from 0.1-1.0 mm, preferably, 0.1 to 0.3 mm, the Amount used in the reaction, will be in the range from 1:5 to 1:50, preferably 1: 20.

Under halogenoalkane acids is either oxohalides acid, such as perchloric acid.

Individual 22R and 22S-epimer, which are formed by acetalization have almost the same solubility characteristics. Accordingly, it may be impossible to divide and to separate them from a mixture of epimeres traditional methods of separation stereoisomers, for example, by fractional crystallization. In order to obtain individual epimere separately, stereoisomeric mixture, in accordance with formula I, above, are subjected to column chromatography; thus separated 22R and 22S-epimer, taking into account their different mobility in the stationary phase. Chromatography can be performed, for example, cross-linked dextranase gels of the type Sephadex-LH, for example, Sephadex LH-20, in connection with a suitable organic solvent as an eluting agent. The Sephadex LH-20, manufactured by the company Pharmacia Fine Chemicals AB, Uppsala, Sweden, is hydroxypropyltrimonium dextranase gel in the form of beads, in which dextranase circuit connected between a transverse relationship with the formation of 3-dimensional spatial polysaccharide grid. As mobile phase were successfully employed in the halogen-substituted ug is a mixture of 20:20:1.

Chromatography can be performed in a different way, on a column filled with particles with reversed phase of, for example, 10 μm-octadecylsilane ( Bondapak C18), or columns Bondapak CN in combination with a suitable organic solvent as mobile phase. Ethanol-water at a ratio of 40-60:60-40 have been successfully used.

Epimere 22R and 22S can also be obtained from the stereoisomeric mixture of a General formula

< / BR>
where

X1and X2have this above definition and R3is the remnant of a carboxylic acid having a straight hydrocarbon chain of 1 to 5 carbon atoms, preferably 21-acetate, after separation by chromatography on Sephadex LH-20 in combination with a suitable solvent or mixture of solvents such as heptane-chloroform-ethanol in the ratio 0-50:50-10:10-1, preferably 20: 20: 1, as mobile phase. Divided and allocated epimere 22R and 22S with the General formula I, above, are subjected to hydrolysis catalyzed by alkali, with the use of hydroxides, carbonates or bicarbonates of alkali metals, e.g. sodium hydroxide or potassium hydroxide, carbonates of sodium or potassium hydroxide or carbonate of sodium or potassium, to obtain epimeres 22 as a catalyst, for example, with hydrochloric acid or sulfuric acid.

Compounds of formula I are prepared in accordance with the methods described in the company's application - in our case, D1093-1SE.

Pharmaceutical drugs.

Compounds of the present invention can be used for a variety of ways for local purposes, depending on the location of inflammation, for example, subcutaneous, parenteral or local destination in the respiratory tract via inhalation. The main purpose of the recipe purpose is to achieve optimal biological suitability active steroid ingredient. In subcutaneous recipes this can advantageously be achieved if the steroid is dissolved in the carrier with a high thermodynamic activity. To do this, use a suitable solvent system, including suitable glycols such as propylene glycol or 1,3-potentially ether and the like, or their combinations with water.

It is also possible dissolution of the steroid, either fully or partially, in the lipophilic phase using a surfactant as a solvent. Skin compositions can be ointments, oil solutions in creams, water-based, aqueous solutions in voennyi active component, may be the dispersed phase as a continuous phase. Steroid may also be present in the above compositions in the form of very finely ground solids.

Steroid aerosols under high pressure are intended for oral or nasal inhalation. The aerosol system is designed so that the dose at one time contained 10-1000 μg, preferably 20 to 250 micrograms of the active steroid. The most active steroids are prescribed in doses of from the lower part of the dose range. Very finely ground steroids consist of particles, mostly smaller than 5 microns, which are suspended in dispergating mixture using dispersant, such as sorbitan-trioleate, oleic acid, lecithin or sodium salt dioctylsulfosuccinate acid.

The steroid can also be assigned by inhalation of a dry powder.

One possibility is mixing very finely ground with steroid substance carrier, such as lactose or glucose. Powder covered synthesised material mixture is distributed in hard gelatin capsules, each containing the desired dose of the steroid. The capsules are then placed in the inhaler for powdered, and medication dose by inhalation Poblenou powder in the balls, which are destroyed in the process of using doses. These balls of powder is filled in a medicinal capacity pump designed for a lot of doses, for example, Turbuhaler. A measuring device measures the desired dose at one time, which is then inhaled by the patient. In this system, a steroid with a substance carrier, or without it is delivered to the patient.

The steroid can also be included in the prescriptions intended for the treatment of intestinal inflammatory diseases either through the mouth or through the rectum. Recipes for insertion through the mouth should be drawn up in such a way that the steroid was delivered to inflamed areas of the intestine. This can be achieved through different combinations of the principles of control over the release of the active substance in the intestine and/or delayed release of the active substance. For drug administration through the rectum is appropriate assignment in the form of an enema.

Working examples.

The invention will be further illustrated by the following non-limiting examples. In these examples to work with preparative chromatography, was used with a flow rate of 2.5 ml/cm2h-1. Molecular weight in all approx the melting points were determined on a microscope Latta-Wetzlar with a hot table. The HPLC analyses (Highly Effective Liquid Chromatography) was performed on a column (Bondapak C18(300x3,9 mm C. D.) with a volumetric flow rate of 1.0 ml/cm2min-1with a mixture of ethanol/water in the ratio between 40:60 and 60:40 as the mobile phase, if not stated another way.

Example 1. 21-tetrahydroxypregna-4-ene-3.20-dione.

A solution of 6,9-debtor-16-hydroxyprednisolone (2.0 g) in 1000 ml of absolute ethanol was added to a solution of sodium chloride Tris/triphenylphosphine/rhodium (2.2 g) in 500 ml of toluene and was hydrogenosomal at room temperature and atmospheric pressure for 7 days. The reaction mixture was evaporated to dryness and added methylene chloride (50 ml). The solid precipitate was collected and washed several times with small portions of methylene chloride to obtain 1.8 g 6,9-debtor-11,16,17, 21-tetrahydroxypregna-4-ene-3.20-dione.

Molecular weight 414 (RASSC. 414,5).

Example 2. 6,9-debtor-11,21-dihydroxy-16,17- [/1-methylethylidene/bis/oxy/]pregn-4-ene-3.20-dione.

A suspension of 0.9 g of the chloride Tris/triphenylphosphine/ rhodium in 250 ml of degassed toluene was hydrogenosomal for 45 min at room temperature and atmospheric pressure. Then the solution was added 1.0 g portinale - 16,17 - acetonide in 100 ml brand is ecografia on silica gel using a mixture of acetone/petroleum ether as mobile phase to remove the main part of the catalyst. The eluate was evaporated, the residue was further purified by chromatography on a column of Sephadex LH-20 (72.5x6.3 cm) using chloroform as mobile phase. Faction 3555-4125 ml was collected and evaporated with the formation of 0.61 g, 6,9-debtor-11,21-dihydroxy-16,17- [/1-methylethylidene/bis/oxy/]pregn-4-ene-3,20-dione. The melting point 146-151oC. []2D5= +124.5oC (c = 0,220; CH2Cl2). Molecular weight of 454 (RASSC. 454.6). Purity: 98.5% (HPLC analysis).

Example 3. (22R) - 16,17-butylidenedioxy-6,9-debtor 11-of-21-dihydroxypregna-4-ene-3,20-dione

To a solution of freshly distilled butanal (0.5 g) and 0.4 ml of perchloric acid (70%) in 100 ml of purified and dried dioxane was added 1.8 g 6,9-debtor-11,16,17,21 - tetrahydroxypregna-4-ene-3,20-dione in small portions with stirring for 30 minutes the Reaction mixture was stirred at room temperature for another 5 hours and Then was added methylene chloride (600 ml) and the solution washed with aqueous potassium carbonate and water and then dried over anhydrous magnesium sulfate. The crude product obtained after evaporation was purified by chromatography on a column of Sephadex LH-20 (76x6.3 cm) using chloroform as mobile phase. Faction 3015-3705 ml was collected and evaporated, receiving 1.5 g /22R/-16,17-butylidene is 4. /22R/-16,17-butylidenedioxy-6,9-debtor-11,21-dihydroxypregna-4-ene-3,20-dione.

6,9-debtor-11,21-dihydroxy-16,17- [/1-methylethylidene/bis/oxy/]pregn-4-ene-3,20-dione (100 mg), 0.03 ml of butanal, 2 ml of fine sand (SiO2) and 4 ml of heptane were mixed at room temperature. Then with vigorous stirring was added perchloric acid (70%, 0.1 ml). The reaction mixture was stirred at room temperature for 5 h, cooled and filtered. The solid precipitate was washed 4 times with 15 ml of an aqueous solution of potassium carbonate (10%), then 4 times in 15 ml of water, and then 4 times was mixed with 25 ml dichloromethane. The combined extracts were washed with water, dried and evaporated. The residue was dissolved in a small amount of dichloromethane and precipitated with petroleum ether (so Kip. 40-60oC) with the formation of 75 mg /22R/ 16,17-butylidenedioxy-6,9-debtor-11,21-digiexpress-4-ene-3,20-dione, mixed with 3% /22S/-epimer. The purity determined by HPLC analysis, was 98%. Molecular weight of 468 (RASSC. resulting in 468.5).

Example 5. /22R/ and /22S/- 16,17-butylidenedioxy-6,9-debtor-11,21-dihydroxypregna-4-ene-3,20-dione.

/22RS/- 16,17-butylidenedioxy-6,9-debtor-11,21-dihydroxypregna-4-ene-3,20-dione 1.5 g was divided into 22R - and 22S-epimer chromatography on a column of Sephadex LH-20 /h.3 cm/ s ispolzovany and one stripped off. Two products besieged from a mixture of methylene chloride with petroleum ether. The product from fraction A (332 mg) methods1H-NMR and mass spectrometry was identified with /22S/- 16,17-butylidenedioxy-6,9-debtor-11,21-dihydroxypregna-4-ene-3,20-dione and the product of the fraction B (918 mg) with its 22R-epimer.

Epimer had the following properties. The 22S epimer: melting point 231-244oC; []2D5= +84.4o/ c= 0.096; CH2Cl2/; molecular weight 468 (RASSC. 468.5). The 22R epimer: melting point 150-56oC; []2D5= +120.0o(c = 0.190; CH2Cl2); the molecular weight of 468 (RASSC. 468.5). The purity of epimeres was determined by HPLC analysis, it was 95.7% for 22S-epimer (containing 1.2% 22R-epimer) and 98.8% for 22R-epimer (containing 0.7% 22S-epimer).

Example 6. /22R/- ,17-butylidenedioxy-6,9-debtor-11,21-dihydroxypregna-4-ene-3,20-dione.

Solution /22R/- ,17-butylidenedioxy-6,9-debtor-11,21-dihydroxypregna-1,4-diene-3,20-dione (4.0 g) and chloride Tris/triphenylphosphine/rhodium (0.40 g) in 150 ml of absolute ethanol was hydrogenosomal at room temperature for 68 hours Then added water (150 ml) and the mixture was filtered through a HVLP filter (0.45 μm). The filtrate was partially evaporated. The precipitate was filtered, receiving 1.48 g of the crude p phase. Faction 3600-4200 ml were collected, one stripped off and further purified on a column of Sephadex LH-20 (75x6.3 cm) using a mixture of heptane:chloroform:ethanol in a ratio of 20:20:1 as mobile phase. Faction 9825-10500 ml was collected and evaporated with the formation of 0.57 g /22R/-16,17-butylidenedioxy-6,9-debtor-11,21-dihydroxypregna-4-ene-3,20 dione. Molecular weight of 468 (RASSC. 468.5). Purity: 96.5% (HPLC analysis).

Other 220 ml of water was added to the filtrate, above, receiving the next portion of the solid product, which after purification on a column of Sephadex LH-20 (75x6.3 cm) using chloroform as mobile phase (fraction 3795 - 4275 ml) was formed 1.04 g /22R/-16,17-butylidenedioxy-6,9-debtor-11,21-dihydroxypregna-4-ene-3,20-dione. Molecular weight of 468 (RASSC. 468.5). The purity of 98.3% (HPLC analysis).

Example 7. 6-fluoro-11,16,17,21-tetrahydroxypregna-4-ene-3,20-dione.

To a suspension of 1.4 g of the chloride Tris/triphenylphosphine/rhodium 300 ml of toluene was added to the solution 1170 mg of 6-fluoro-11,16,17,21-tetrahydroxypregna-1,4-diene-3,20-dione in 250 ml of absolute ethanol. The mixture was hydrogenosomal 22 h at room temperature and atmospheric pressure and evaporation. The residue was besieged associationoutdoorboard-fluoro-11,16,17,21-tetrahydroxypregna-4-ene-3,20-dione-11,21-dihydroxypregna-4-ene-3,20-dione.

6-fluoro-11,16,17,21-tetrahydroxypregna-4-ene-3,20-dione (308 mg) was added in portions to a solution of butanal (115 mg) and 70% perchloric acid (0.2 ml) in 50 ml of dioxane. The reaction mixture was stirred at room temperature for 6 hours Then was added methylene chloride (200 ml), the solution washed with 10% potassium carbonate solution, water and dried. The residue after evaporation was purified on a column of Sephadex LH-20 /87x2.5 cm/ using chloroform as mobile phase. Faction 420-500 ml were collected and one stripped off with the formation of 248 mg /22RS/-16,17-butylidenedioxy-6-fluoro-11,21-dihydroxypregna-4-ene-3,20 dione. The melting point 85-96oC. []2D5= +119.8o(c = 0.192; CH2Cl2). Molecular weight of 450 (RASSC. 450.6). Purity: 96.1% (HPLC analysis). The distribution between the 22R and 22S-epimerase was 59/41 (HPLC analysis).

Primer./22R/and/22S/-butylidenedioxy-6-fluoro-11,21-dihydroxypregna-4-ene-3,20 dione.

/22RS/-16,17-butylidenedioxy-6-fluoro-11,21-dihydroxypregna-4-ene-3,20-dione (225 mg) was divided into portions preparative HPLC on a column (Bondapak C18(150x19 mm) using a mixture of ethanol:water in a ratio of 40:60 as the mobile phase. Fractions concentrated to about 265 ml, /A/ and 310 ml /B/, respectively, were collected and one stripped off. After deposition of a mixture of chlor-3,20-dione. The melting point 180-192oC.

[]2D5= +138.9oC (c = 0.144; CH2Cl2). Molecular weight of 450 (RASSC. 450.6). Purity: 99.4% (HPLC analysis).

Fraction B after deposition formed 62 mg /22S/-16,17-butylidenedioxy-6-fluoro-11,21-dihydroxypregna-4-ene-3,20-dione. The melting point 168-175oC. []2D5= +103.7o(c = 0.216; CH2Cl2). Molecular weight of 450 (RASSC. 450.6). Purity: 99,5% (HPLC analysis).

Example 10. /22R/ and /22S/-21-acetoxy-16,17-butylidenedioxy-6-fluoro-11-hydroxypregn-4-ene-3,20-dione.

/22RS/-16,17-butylidenedioxy-6-fluoro-11,21-dihydroxypregna-4-ene-3,20-dione (68 mg) was dissolved in 1 ml of pyridine. Was added acetic anhydride (1 ml) and the reaction mixture was stirred at room temperature for 1 h, then was poured into ice water and was extracted with 3 times 25 ml of methylene chloride. The extract was dried and evaporated. The residue was chromatographically on a column of Sephadex LH-20 (89x2.5 cm) using a mixture of heptane:chloroform: ethanol in a ratio of 20: 20: 1 as mobile phase. Faction 380-400 ml, /A/ and 420-440 ml /B/ were collected and one stripped off.

After deposition of a mixture of methylene chloride-petroleum ether fraction formed A 14 mg /22S/-21-acetoxy-16,17-butylidenedioxy-6-UB>Cl2). Molecular weight of 492 (RASSC. 492.6). Purity: 97.5% (HPLC analysis).

Fraction B after deposition formed 20 mg /22R/-21-acetoxy-16,17-butylidenedioxy-6-fluoro-11-hydroxypregn-4-ene-3,20-dione. The melting point 169-172oC. []2D5= +139.0o(C = 0.200; CH2Cl2). Molecular weight of 492 (RASSC. 492.6). Purity: 97.9% (HPLC analysis).

Example 11. /22R/-16,17-butylidenedioxy-6-fluoro-11,21-dihydroxypregna-4-ene-3,20-dione.

To a solution of 20 mg /22R/-21-acetoxy-16,17-butylidenedioxy-6-fluoro-11-hydroxypregn-4-ene-3,20-dione in 2 ml of ethanol was added 2 ml of 2M hydrochloric acid. After stirring at 60oC for 5 h, the reaction mixture was neutralized with a saturated aqueous solution of sodium bicarbonate and was extracted with 3 times 25 ml of methylene chloride. The combined extracts were washed with water, dried and evaporated. The residue was purified on a column of Sephadex LH-20 (87x2.5 cm) using chloroform as mobile phase. Faction 460-515 ml was collected and evaporated with the formation of 8 mg /22R/-16,17-butylidenedioxy-6-fluoro-11,21-dihydroxypregna-4-ene-3,20-dione. Molecular weight of 450 (RASSC. 450.6). The purity of 98.4% (HPLC analysis).

Example 12. /22S/-16,17-butylidenedioxy-6-fluoro-11,21-dihydroxypregna-4-ene-3,20-dione.

To rest what Laney acid. Reaction, separation and purification were performed as in example 1. Faction 455-510 ml was collected and evaporated with the formation of 7 mg /22S/-16,17-butylidenedioxy-6-fluoro-11,21-dihydroxypregna-4-ene-3,20-dione. Molecular weight of 450 (RASSC. 450.6). Purity: 98.6% (HPLC analysis).

Example 13. 21-tetrahydroxypregna-4-ene-3,20-dione.

A suspension of 3.0 g of chloride Tris/triphenylphosphine/rhodium in 1000 ml of degassed toluene was hydrogenosomal for 45 min at room temperature and atmospheric pressure. Then solution was added 5.0 g of triamcinolone in 500 ml of absolute ethanol and hydrogenation continued for another 48 hours the Reaction mixture was evaporated to dryness and suspended in 50 ml of methylene chloride. After filtration of the solid phase is repeatedly washed with small portions chloride methylenedioxyaniline.G-fluoro-11,16,17,21-tetrahydroxypregna-4-ene-3,20-dione. Molecular weight of 396 (RASSC. 396.5)16,17-butylidenedioxy-9-fluoro-11,.

Primer./22RS/-9-fluoro-11,16,17,21-dihydroxypregna-4-ene-3,20-dione.

To a solution of freshly distilled butanal (100 mg) and 0.2 ml of perchloric acid (70%) in 50 ml of purified and dried dioxane was added 16,17-butylidenedioxy-9-fluoro-11, 21-tetrahydroxypregna-4-ene-3,20-dione (340 mg) in small portions with stirring tilen (200 ml), the solution was washed with an aqueous solution of potassium carbonate and water and dried over anhydrous magnesium sulfate. The crude product obtained after evaporation was purified on a column of Sephadex LH-20 (72.5x6.3 cm) using chloroform as mobile phase. Faction 2760-3195 ml were collected and one stripped off with the formation of 215 mg /22RS/-16,17-butylidenedioxy-9-fluoro-11,21-dihydroxypregna-4-ene-3,20-dione. Molecular weight of 450 (RASSC. 450.6). Purity: 97.4% (HPLC analysis).

Example 15. /22R/ and /22S/-16,17-butylidenedioxy-9-fluoro-11,21-dihydroxypregna-4-ene-3,20-dione.

/22RS/-16,17-butylidenedioxy-9-fluoro-11,21-dihydroxypregna-4-ene-3,20-dione (200 mg) was separated by chromatography on a column of Sephadex LH-20 (76x6.3) using a mixture of heptane-chloroform-ethanol /20:20:1 as mobile phase. Faction 7560-8835 ml, /A/ and 8836-9360 ml /B/ were collected and one stripped off. The product of the fraction A /128 mg/ methods1H-NMR and mass spectrometry was identified with /22S/-[]2D521-dihydroxypregna-4-ene-3,20-dione and the product of the fraction B (50 mg) - with its 22R-epimer.

Epimer had the following properties. The 22S epimer: melting point 180-190oC; []2D5= +105,6o(c = 0,214; CH2Cl2); the molecular weight of 450 (RASSC. 450,6). The 22R epimer: point plavini Rasch. 450,6). The purity of epimeres was determined by HPLC analysis, it was $ 97.6% for 22S-epimer (containing 1.8% 22R-epimer) and 98.2% for 22R-epimer (containing 0.8% 22S-epimer).

Example 16. Pharmaceutical drugs.

The following non-limiting examples illustrate the recipes, designed for different topically-active forms of assignment. The number of active steroid in skin recipes is usually 0.001-0.2% (weight/volume), preferably 0.01-0.1% (weight/volume).

Recipe 1. Ointment, g:

Steroid, very finely chopped - 0.025

Liquid paraffin - 10.0

Soft white paraffin To 100.0

Recipe 2. Ointment, g:

Steroid - 0.025

Propylene glycol 5.0

Sorbitan-sesquioleate - 5.0

Liquid paraffin - 10.0

Soft white paraffin To 100.0

Recipe 3. The oil solution in cream, water-based, g:

Steroid - 0.025

Cetanol - 5.0

Glycerol-monostearate - 5.0

Liquid paraffin - 10.0

Cetomacrogol 1000 - 2.0

Citric acid 0.1

Sodium citrate - 0.2

Propylene glycol 35.0

Water Up to 100.0

Recipe 4. The oil solution in cream, water-based, g:

Steroid finely chopped - 0.025

White soft paraffin - 15.0

Liquid paraffin - 5.0

Cetanol - 5 the I acid - 0.1

Sodium citrate - 0.2

Water Up to 100.0

Recipe 5. Aqueous solution in the cream is oil-based, g:

Steroid - 0.025

White soft paraffin - 35.0

Liquid paraffin - 5.0

Sorbitan-sesquioleate - 5.0

Sorbic acid - 0.2

Citric acid 0.1

Sodium citrate - 0.2

Water Up to 100.0

Recipe 6. The lotion.

Steroid - 0.25 mg

Isopropyl alcohol is 0.5 mg

Carboxyquinolone 3 mg

NaOH - C. N.

Water To 1.0 l

Recipe 7. Suspension for injections, mg:

Steroid, very finely chopped - 0.05-10

Sodium-carboxymethylcellulose - 7

NaCl - 7

Polyoxyethylene/20/sorbitan-monooleate - 0.5

Phenyl-carbinol - 8

Sterile water To 1.0 ml

Recipe 8. Aerosol for inhalation through the mouth and through the nose,%/:

Steroid, very finely chopped - 0.1

Sorbitan-trioleate - 0.7

Trichlorofluoromethane - 24.8

Dichlorotetrafluoroethane - 24.8

DICHLORODIFLUOROMETHANE - 49.6

Recipe 9. The solution for spraying, g:

Steroid - 7.0

Propylene glycol 5.0

Water - To 10.0

Recipe 10. Powder for inhalation.

Gelatin capsules filled with a mixture, mg:

Steroid, very finely chopped - 0.1

Lactose - 20

Powder Dehaene in the balls, filled reusable nebulizer for powder. Each dose contains:

Steroid, very finely chopped - 0.1 mg

Recipe 12. Powder for inhalation, mg:

Powder, formed into balls, filled reusable nebulizer for powder. Each dose contains:

Steroid, very finely chopped - 0.1

Lactose, very finely chopped - 1

Recipe 13. Capsules for the treatment of small intestine, mg:

Steroid - 1.0

Sugar balls - 321

Aquacoat ECD 30 - 6.6

Acetyltributyl-citrate - 0.5

Polysorbate 80 - 0.1

Eudragit L100-55 - 17.5

Triethylcitrate - 1.8

Talc - 8.8

Antifoam MMS 0.01

Recipe 14. Capsules for the treatment of colon, mg:

Steroid - 2.0

Sugar balls - 305

Aquacoat ECD 30 - 5.0

Acetyltributyl - 0.4

Polysorbate 80 - 0.14

Eudragit NE30D - 12.6

Eudragit S100 - 12.6

Talc - 12.6

Recipe 15. Enema through the rectum, mg

Steroid - 0.02

Sodium-carboxymethylcellulose - 25

TLD-sodium salt of ethylenediaminetetraacetic acid 0.5

Methyl-parahydroxybenzoate - 0.8

Propyl-parahydroxybenzoate - 0.2

Sodium chloride - 7.0

Anhydrous citric acid - 1.8

Polysorbate 80 - 0.01

Purified water To 1.0 ml

A significant portion of inhaled corticosteroids is deposited in the throat, and later when ingested is in the gut. This part contributes to the unwanted side effects of steroid, because it operates outside the area intended for treatment (light). Therefore, it is advantageous to use GCS with high local anti-inflammatory activity in the lungs, but that they had little effect GKS after administration by mouth. Therefore, studies were designed to determine the effect caused by GCS after local application in the lungs, and after the appointment through the mouth; the difference between the effect of glucocorticosteroid in the treated lung area and outside this area was tested as follows.

Biological tests

A. the Model to verify that the desired local anti-inflammatory action on the mucous membranes of the respiratory tract (left lobe of the lungs).

Rats Sprague Dawley (250 g) was slightly anestesiologi using afrana, and trial glucocorticosteroid drug (suspended in salt solution) in an amount of 0.5 ml/kg was injected directly into the left lobe of the lungs. After 2 h the suspension Sephadex (5 mg/kg in a volume of 1 ml/kg) under weak ane the lobes of the lungs. After 20 h, the rats were scored, the left lobes of the lungs were excised and weighed. The control group received saline solution instead of the drug of glucocorticosteroid and a salt solution instead of suspension Cephadex in order to determine the weight swelling from Sephadex, raw medicine, and the weight of a normal lung.

B. Model validation unwanted systemic effects of glucocorticosteroid taken through the mouth.

Rats Sprague Dawley (250 g) was slightly anestesiologi using afrana and after that they were given (by mouth) trial GKS-the drug in a volume of 0.5 ml/kg After 2 h the suspension Sephadex (5 mg/kg in a volume of 1 ml/kg) was poured into the puncture of the trachea above the bifurcation, so that the suspension has reached both the left and right lobes of the lungs. After 20 h, the rats were killed and weighed lobes of the lungs. The control group received saline solution instead of the drug of glucocorticosteroid and a salt solution instead of suspension Cephadex in order to determine the weight swelling from Sephadex, raw medicine, and normal weight.

Results of the comparative study are shown in table. Pharmacological profile of tested compounds of the invention were compared with those budezonida. The results demonstrate that the compound C. the more, the results also demonstrate higher selectivity in respect of the lungs checked compounds of the invention in comparison with the selected connection of the prior art, since the dose required to suppress edema /ED50/ in the appointment through the mouth of the aforementioned compounds, 32 times higher, and have 13 times more budezonida, compared with a dose of tested drugs to suppress edema in the local application in the lung (Budesonide: 4000 and 300 nmol/kg; the substance from example 6: 320, and 10 nmol/kg, respectively).

Thus, it can be concluded that the compounds of the invention are well suited for the topical treatment of inflammatory skin lesions and various body cavities (e.g., lungs, nose, intestines and joints).

Table

Action check glucocorticosteroids on the model of edema in rats caused by Sephadex. The results are given in relation to the corresponding control group, which gave the Sephadex.

1. 22R - or 22S-epimer compounds of General formula I

< / BR>
where X1a fluorine atom;

X2is a hydrogen atom or a fluorine atom.

2. Connection on p. 1, representing 22R - or 22S-epimer patterns

< / BR>

4. The compound according to any one of paragraphs.1 to 3, with anti-inflammatory or anti-allergic properties.

5. The method of obtaining the compounds of formula I on p. 1, characterized in that the compound of the formula

< / BR>
where X1and X2are specified in paragraph 1 values;

R - each OH-group or together they group

< / BR>
subjected to interaction with the aldehyde of the formula

HCOCH2CH2CH3,

then epimeno mixture is separated into its stereoisomeric components.

6. The method according to p. 1, characterized in that the compound of the formula

< / BR>
or

< / BR>
where X1and X2are specified in paragraph 1 values;

R3- the remainder of the carboxylic acid having a straight hydrocarbon chain with 1 to 5 carbon atoms,

subjected to hydrolysis.

7. The pharmaceutical composition exhibiting anti-inflammatory and anti-allergic effect, comprising as active substances derived pregnene-4 and a pharmaceutically acceptable carrier, characterized in that as a derived pregnene-4, it contains the (22R)- 16,17 - butylidenedioxy - 6,9 - debtor-11,21 - dihydroxy-pregn-4-ene-3,20-dione in an effective amount.

8. The composition according to p. 7, otlichayuschih diseases of mammals, including humans, such as inflammatory bowel disease, wherein the patient in need of treatment is prescribed for oral administration (22R) -16,17 - butylidenedioxy-6,9 - debtor-11,21 - dihydroxy-pregn-4-ene-3,20-dione in an effective amount.

 

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17th-butylidenedioxy - 11, 21-dihydroxypregna-1,4-diene-3,20-dione" target="_blank">

The invention relates to a new manufacturing process (22R, S)-1617th-butylidenedioxy-11, 21-dihydroxypregna-1,4 - diene-3,20 - dione(budezonida)

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The invention relates to the field of synthesis of steroid compounds

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< / BR>
where

if OR3is set tothen

R1, R2and R3independently from each other represent a hydrogen atom, acyl groupin which R4represents an organic residue with a number of carbon atoms up to 11, or a residue -/CH2/nCOOH carboxylic acid, with n=1-4, and, in addition, R1denotes benzyl, C1-C8-alkilany or C3-C5-cycloalkenyl balance, and

if OR3is in "beta", then

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< / BR>
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The invention relates to inhibitors of steroid alpha-reductase have the following formula:

< / BR>
where Y is oxygen or sulfur; R is the group: (a) OR4where R4is hydrogen or C1-C6alkyl group; b)where each of R5and R6independently hydrogen or C1-C6alkyl group;)where R7is hydrogen or C1-C6alkyl group, W is a group; (I)where R8- C1-C6alkyl group, a C5-C6cycloalkyl group, C6-C9cycloalkylation group, phenyl group or benzilla group; or (II)where R9- C1-C6alkyl group or a C5-C6cycloalkyl group, or (III)where R5and R6defined above; g)where each of R10and R11- independently hydrogen or C1-C6an alkyl group or both in the static ring, optionally comprising at least one additional heteroatom selected from oxygen and nitrogen; n is an integer from 2 to 4; R1is hydrogen, C1-C6alkyl group, a C5-C6cycloalkyl group, C6-C9cycloalkylation group or aryl group; each of R2and R6independently selected from the group consisting of hydrogen, C1-C6of alkyl, C5-C6cycloalkyl, C6-C9cycloalkenyl and aryl, or R2and R3together with the nitrogen atom to which they are bound, form pentatominae or hexatone rich heterophilically ring, optionally comprising at least one additional heteroatom selected from oxygen and nitrogen; the symboldenotes a single or double bond, provided that when is a double bond, the hydrogen in the 5-position is absent, and its pharmaceutically acceptable salts

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to the substituted 4-benzylaminoquinolines and their heteroanalogs of the general formula (I): P-L-G (I) wherein G means compound of the formula: G(I) wherein K means -OR(7), -NH-CH2-CH2-SO3H, -NH-CH2-CO2H wherein R(7) means hydrogen atom, CH3; R1-R6 mean independently of one another hydrogen atom, -OR(10), -R(10) being one of residues R1-R6 means a bond with L always; R(10) means hydrogen atom, (C1-C4)-alkyl; L means (C1-C15)-alkyl being one or some structural CH2-fragments can be replaced for -C≡C-, -NR(11)-, -CO-, -O- wherein R(11) means hydrogen atom; P means: or wherein A means nitrogen atom (N); B means CH; D means CH; E means CH; R16-R24 mean independently of one another hydrogen atom, F, Cl atoms, (C1-C4)-alkyl being alkyl residues can be mono- or multiple-substituted with fluorine atom, NR(25)R(26), OR(25), COR(25), COOR(25), CONR(25)R(26) being one of residues R16-R(24) means a bond with L always; R25 and R26 mean independently of one another hydrogen atom, (C1-C4)-alkyl or benzyl. Also, invention relates to their pharmaceutically acceptable salts. Also, invention relates to a method for their preparing and to a drug based on thereof for prophylaxis of supersaturation of bile with cholesterol. Invention provides preparing new compounds and a drug based on thereof that can be used for prophylaxis and treatment of patients suffering with gallstones.

EFFECT: improved preparing method, valuable medicinal properties of compounds and drugs.

10 cl, 32 ex

FIELD: medicine, endocrinology, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising drospirenone as the first active agent in the amount corresponding to daily dose from 2 to 4 mg in administration of the composition, and ethynylestradiol as the second active agent in the amount corresponding to daily dose from 0.01 to 0.05 mg in combination with one or some pharmaceutically acceptable vehicles or additives. Drospirenone as a component of the pharmaceutical composition is in the finely divided form. The preparation comprises some separately packages and individually taken medicinal units placed in the unit package and designated for oral administration for at least 21 days at a time and indicated daily medicinal units comprise the combination of drospirenone and ethynylestradiol. The preparation can comprise 7 and less daily doses no containing any active agent or containing ethynylestradiol only. The combination of ethynylestradiol and drospirenone provides the safety contraceptive activity due to using the maximal dose of drospirenone being without adverse effects, in particular, excessive diuresis.

EFFECT: improved and valuable properties of combination.

34 cl, 5 dwg, 5 ex

FIELD: medicine.

SUBSTANCE: method involves carrying out laparoscopy and administering Danazol at a dose of 400 mg twice a day for 6 months. Danazol treatment being over and normal prolactinemia being observed in biphasic menstrual cycle, Parlodel is administered at a dose of 2.5 mg twice a day for three menstrual cycles long period.

EFFECT: enhanced effectiveness in normalizing hormone background and pregnancy taking place.

FIELD: pharmaceutical industry, medicine.

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EFFECT: method for replacement hormonotherapy in women of improved efficiency.

46 cl, 7 ex

FIELD: organic chemistry, steroids, biology.

SUBSTANCE: invention relates to steroid compounds of the general formula (X):

wherein in fragment of the formula XA:

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EFFECT: improved methods of synthesis, valuable biological properties of compounds.

16 cl, 8 dwg, 2 tbl, 30 ex

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